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Τρίτη 4 Οκτωβρίου 2022

Immunomodulatory effect of IL‐1RA in LPS activated macrophage/dental pulp stem cells co‐culture

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Abstract

Aims:

Lipopolysaccharides (LPS) activated human dental pulp stem cells (hDPSCs) and macrophage co-cultures showed downregulated TNF-α secretion that is modulated by hDPSCs through IDO axis, whereas the secretory levels of IL-1β remained unchanged. Therefore, sustained production of IL-1β could contribute to progressive dental pulp inflammation. However, the role of IL-1 receptor antagonists (IL-1RA) in downregulating the secretion of IL-1β and TNF-α in LPS activated M0/M1/M2 macrophage and hDPSCs co-culture has not been studied yet. Therefore, the aim of the present study is to determine the immunomodulatory role of blocking IL-1 receptors in DPSCs macrophage co-culture activated with LPS.

Methodology:

Human monocytic cell line THP-1 was polarised to M0, M1, and M2 macrophages and co-cultured with hDPSCs. The viability of the co-cultured cells was assessed by apoptosis assay. Co-cultures were activated with LPS followed by the assessment of gene expression and protein levels of IL-1β and TNF-α with and without IL-1RA blocking via qRT-PCR and cytokine flex assay by flow cytometry. Data from three separate experiments was analysed using One-way ANOVA followed by Tukey's Post-hoc test and a p value of <0.05 was considered statistically significant.

Results:

THP-1 derived M0, M1, and M2 macrophages co-cultured with hDPSCs showed spindle and round-shaped cells, with > 90% viability when assessed by apoptosis assay. Inflammatory TNF-α and IL-1β profile in stimulated co-cultures showed upregulated IL-1β whereas TNF-α was downregulated (p< 0.05). Anti-inflammatory gene expression levels of IL-10, TGF-β were downregulated (p< 0.05). Blocking with IL-1RA resulted in remarkable decrease of IL-1β at the gene expression and protein production levels while TNF-α levels remained low (p< 0.05). Levels of anti-inflammatory cytokine IL-10 showed no significant difference.

Conclusion:

Blocking the IL-1 receptor in hDPSCs and macrophage (M0, M1, M2) co-cultures activated with LPS resulted in down regulation of inflammatory cytokines IL-1β and TNF-α. These findings highlight the immunomodulatory effect of IL-1RA in inflammatory conditions of dental pulp infections.
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Magnetic Resonance Imaging Directed Surgical Decision Making for Lateral Pelvic Lymph Node Dissection in Rectal Cancer After Total Neoadjuvant Therapy (TNT)

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imageObjective: Lateral pelvic lymph node (LPLN) metastases are an important cause of preventable local failure in rectal cancer. The aim of this study was to evaluate clinical and oncological outcomes following magnetic resonance imaging (MRI)-directed surgical selection for lateral pelvic lymph node dissection (LPLND) after total neoadjuvant therapy (TNT). Methods: A retrospective consecutive cohort analysis was performed of rectal cancer patients with enlarged LPLN on pretreatment MRI. Patients were categorized as LPLND or non-LPLND. The main outcomes were lateral local recurrence rate, perioperative and oncological outcomes and factors associated with decision making for LPLND. Results: A total of 158 patients with enlarged pretreatment LPLN and treated with TNT were identified. Median follow-up was 20 months (interquartile range 10–32). After multidisciplinary review, 88 patients (56.0%) underwent LPLND. Mean age was 53 (SD±12) years, and 54 (34.2%) were female. Total operative time (509 vs 429 minutes; P=0.003) was greater in the LPLND group, but median blood loss (P=0.70) or rates of major morbidity (19.3% vs 17.0%) did not differ. LPLNs were pathologically positive in 34.1%. The 3-year lateral local recurrence rates (3.4% vs 4.6%; P=0.85) did not differ between groups. Patients with LPLNs demonstrating pretreatment heterogeneity and irregular margin (odds ratio, 3.82; 95% confidence interval: 1.65–8.82) or with short-axis ≥5 mm post-TNT (odds ratio 2.69; 95% confidence interval: 1.19–6.08) were more likely to undergo LPLND. Conclusions: For rectal cancer patients with evidence of LPLN metastasis, the appropriate selection of patients for LPLND can be facilitated by a multidisciplinary MRI-directed approach with no significant difference in perioperative or oncologic outcomes.
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Polyethylenglycol – Freund oder Feind?

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Laryngorhinootologie 2022; 101: 784-786
DOI: 10.1055/a-1861-7047

Anaphylaktische Reaktionen nach Impfungen sind selten. Zwei Fälle von Reaktionen nach der Pfizer-BioNTech-Covid-19-Vakzine, BNT162b2, wurden aus dem UK berichtet, weitere 19 aus den USA. Als möglicher Auslöser wurde Polyethylenglycol (PEG) angeschuldigt. Pegylierung ist ein üblicher Vorgang in der Impfstoffherstellung, um die Substanzen vor schnellem immunologischem Abbau zu schützen. PEG ist ein Polyether (Synonyme z. B. Laureth-9, Polidocanol, Thesit, Macrogol) und findet sich in Kosmetika, Körperpflegeprodukten, Nahrungsmitteln, Liposomen und Nanopartikeln als Drug-Delivery-Systeme für Medikamente und als osmotisches Laxans vor Gastro-/Koloskopien. IgM-Antikörper auf PEG werden bei 70% der Bevölkerung nachgewiesen. Bei 2 Fällen von Soforttyp-Reaktionen auf PEG fanden sich IgE-Antiköper, bei anderen Medikamentengaben mit PEG geht man von pseudoallergischen Reaktionen über die Komplement-Aktivierungs-related Pseudoallergie (CARPA) aus. In Relation zum weit verbreiteten Einsatz von PEG sind die Impfreaktionen sehr selten und aktuell kein Grund, Allergiker oder Menschen mit Anaphylaxien bei entsprechenden Vorsichtsmaßnahmen auf bekannte Auslöser auszuschließen. Aufgrund der Meldepflicht (Gesundheitsamt und Arzneimittelkommission der deutschen Ärzteschaft) ist bald mit weiteren Erkenntnissen zu rechnen.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text
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Δευτέρα 3 Οκτωβρίου 2022

Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a Mendelian randomization study

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Abstract
Background
Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight.
Methods
We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH; n = 872) and UK Biobank (UKB; n = 133 187). We conducted two-sample MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs); n = 288 649 European ancestry] on offspring birthweight (n = 406 063 European ancestry; maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-sample MR in UKB women (n = 199 768).
Results
Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: –50, 6); P = 0.13] and UKB [–28 g (95% CI: –31, –25); P = 1.8 × 10–75]. The MR causal effect estimate was directionally consistent, but smaller [–11 g (95% CI: –25, 3); PIVW = 0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1); P = 7.8 × 10–22], consistent with that previously published in women and men.
Conclusion
The marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweigh t. Maternal urate levels are unlikely to be an important contributor to offspring birthweight.
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Κυριακή 2 Οκτωβρίου 2022

Management of Low-Grade Gliomas – Extent of Resection Matters But Not All Tumours Are Amenable to Surgery

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Abstract
AIMS
To present and review our experience in the management of low-grade gliomas.
METHOD
Retrospective case note review of all patients with WHO grade 2 glioma from 2011 to 2018 (based on WHO criteria at time of diagnosis). Data collected on demographics, presentation, location, initial management, histology, treatment, progression free (PFS) and overall survival (OS).
RESULTS
130 eligible patients. Median follow 4.6 years (up to 10.5). Median age 40 years (range: 18-83). There were 70 (53.8%) astrocytomas, 44 (33.8%) oligodenrogliomas, 16 (12.3%) oligoastrocytomas. 66%(n=86) presented with seizures, 10.7%(n=14) with sensory symptoms, 8.5%(n=11) with speech disturbance, 5.3%(n=4) with motor symptoms and 12.3%(n=16) were identified incidentally. 50.1%(n=65) were frontal, 27.7%(n=36) temporal and 9.2%(n=12) parietal. 1st line treatment was resection in 70.7%(n=92), biopsy in 23.8%(n=31) and observation in 4.6%(n=6). 15.4 %(n=20) received adjuvant radiotherapy alone and 6.1%(n=8) received adjuvant radiotherapy followed by chemotherapy . At first recurrence, 31.6%(n=12) received further surgery and 95%(n=38) received radiotherapy and/or chemotherapy . Median PFS from 1st line treatment 66, 44 and 33 months for gross total resection (GRT), subtotal resection (STR), and biopsy respectively. Overall survival was 95.1%, 79.3% and 69.% for GTR, STR and biopsy respectively.
CONCLUSION
Management of low-grade gliomas remains challenging. Extent of resection impacts prognosis but not all patients have gliomas amenable to surgery. The effects of chemoradiotherapy will be presented in future meetings as this is an ongoing project.
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Stereotactic Radiosurgery for Brainstem Metastases

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Abstract
AIMS
Limited data exists on outcomes following SRS for brainstem metastases (BSM). The purpose of this audit was to explore the use of SRS using Cyberknife for BSM at a single centre; reporting rates of toxicity and survival outcomes.
METHOD
Patients undergoing SRS for BSM from 2013 to 2021 were identified from a prospective database. Clinical characteristics were collected including; gender, age, histology and KPS. The use of previous WBRT, the volume and the dose delivered to the BSM were also recorded. All target volumes were peer reviewed by a neuro-radiologist.
RESULTS
41 patients with a BSM were identified. The median age was 62 years (range 35-78). Histology was lung 15 (36.6%), breast 13 (31.7%) and other 13(31.7%). The median brainstem target volume was 0.36cc (range 0.01 – 5.63cc). 32 patients had single fraction (dose range 14.5 to 18Gy) and 9 patients had 3 fractions (dose range 17-24Gy). 7 patients had p revious WBRT. Median overall survival was 242 days (range 19-1213). A radiological response or stable disease was seen in 26 out of 30 patients with post SRS imaging available for review. 2 patients developed a 6th nerve palsy. 12 patients required a prolonged course of dexamethasone. No statistically significant relationship was observed between patient age, brainstem lesion size or fractionation and the need for prolonged use of dexamethasone but there was a trend with lung cancer patients requiring prolonged dexamethasone (p=0.06).
CONCLUSION
Brainstem SRS is viable option with an acceptable late toxicity profile. Updated information on survival and local control will be presented.
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Partial laryngectomy for naïve pT3N0 laryngeal cancer: Systematic review on oncological outcomes

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Abstract

The first aim was to define the oncologic outcomes of open partial laryngectomy (OPL) in naïve pT3 laryngeal cancer. The second aim was to analyze the outcomes after OPL versus total laryngectomy (TL). A literature search was conducted in three databases (MEDLINE, EMBASE, and Cochrane Library) until January 2022. In 805 patients treated with OPL, 5-year OS, DSS, DFS and LFS were 80.5% (95% CI 70.6–87.6), 83.4% (95% CI 75.7–89), 77.4% (95% CI 66.3–85.7) and 77.9% (95% CI 68.7–85), respectively. Three articles compared TL versus OLP: 5-year OS, DSS and DFS risk difference were 0.100 (95% CI −0.092 to 0.291), 0.067 (95% CI −0.085 to 0.220) and 0.018 (95% CI −0.164 to 0.201) respectively. OPL for selected pT3 laryngeal cancer is able to guarantee a high percentage of oncological success. Accurate patient selection is of utmost importance to differentiate advanced disease amenable to conservative surgery.
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Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome

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Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome

The brains of 8-week-old wildtype (WT) mice (left) and mice carrying mutations (D1113H) in the ADAR1 gene (right) probed for expression of Interferon Stimulated Gene 15 (ISG-15) using In situ hybridization (red). WT mice show little to no expression of ISG-15 while ADAR1 mutant mouse brain shows a broad and chaotic distribution of expression throughout the brain (8 of many foci circled).


Abstract

Chronic inflammation is frequently invoked as a mechanism of neurodegeneration and yet inflammatory cell infiltrates are seldom seen in brains of these disorders. Different disciplines utilize different technologies and methodologies to describe what is immunologically defined as the innate immune response (IIR). We examined murine models of the human neurodegenerative disease Aicardi–Gutiérrez Syndrome, where an IIR is initiated by aberrant RNA metabolism secondary to a mutation in adenosine deaminase acting on RNA gene (ADAR1). We previously showed that these mice demonstrated a deficit in RNA editing that lead to MDA-5 mediated RNA sensing pathway activation of the IIR with massive interferon stimulated gene transcription and translation. As early as 2 weeks of age, in situ hybridization demonstrated that different central nervous system (CNS) cell lineages expressed very high levels of distinct interferon stimulated genes (ISGs) in the absence of interferon and absence of immune cell infiltrates. We have expanded these studies to more completely describe the breadth of ISG expression systemically and in CNS using double label in situ hybridization. Within the CNS aberrant ISG expression was mostly limited to neurons, microglia, ependyma, choroid plexus, and endothelial cells with little expression in oligodendroglia and astrocytes except for STAT1. Wild type controls showed a similar pattern of ISG expression but only in aged mice and at levels minimally detectable by in situ hybridization. Despite months of elevated ISG expression in mutant mice, there was essentially no inflammatory infiltrate, no interferon production and minimal glial reaction. Histomorphological neurodegenerative pathology of ventricular dilatation and deep gray matter mineralization were evident in mutant mice 8–13 months of age but this did not show a spatial relationship to ISG expression. This IIR without immune cell infiltration leads to neurodegeneration through non-c anonical pathways that may accentuate normal aging pathways.
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Molecular landscapes of longitudinal NF2/22q and non‐NF2/22q meningiomas show different life histories

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Abstract

Recurrence is a major complication of some meningiomas. Although there were many studies on biomarkers associated with higher grades or increased aggressiveness, few studies specifically examined longitudinal samples of primary meningiomas and recurrences from the same patients for molecular life history. We studied 99 primary and recurrent meningiomas from 42 patients by FISH for 22q, 1q, 1p, 3p, 5q, 6q, 10p, 10q, 14q, 18q, CDKN2A/B homozygous deletion, ALT (Alternative Lengthening of Telomere), TERT re-arrangement, targeted sequencing and TERTp sequencing. Although NF2 mutation and 22q were well known to be aetiological events in meningiomas, we found that in these paired meningiomas, combining the two events resulted in an NF2/22q group (57 tumors from 25 patients) which were almost mutually exclusive with those cases without these two changes (42 tumors from 17 patients) for NF2/22q. No other molecular changes were totally unique to NF2/22q or non-NF2/22q tumors. For molecular evolution, NF2/22q meningiomas had higher cytogenetic abnormalities than non-NF2/22q meningiomas (p = 0.003). Most of the cytogenetic changes in NF2/22q meningiomas were present from the outset whereas for non-NF2/22q meningiomas, cytogenetic events were uncommon in the primary tumors and most were acquired in recurrences. For non-NF2/22q tumors, CDKN2A/B homozygous deletion, 1q gain, 18p loss, 3p loss, and ALT were preferentially found in recurrences. Mutations were largely conserved between primary and recurrent tumors. Phylogenetic trees showed 11/11 patients with multiple recurrent tumors had a conserved evolutionary pattern. We conclude that for molecular life history, NF2 and 22q should be regarded as a group. NF2/22q recurring meningiomas showed more cytogenetic abnormalities in the primary tumors, whereas non-NF2/22q meningiomas showed C DKN2A/B deletion and other cytogenetic abnormalities and ALT at recurrences. Although chromosome 1p loss is a known poor prognostic marker in meningiomas, it was also associated with a shorter TBR (time between resection) in this cohort (p = 0.002).
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Genetic Polymorphism in the Tumor Necrosis Factor Alpha gene (G‐308A) is associated with Persistent Apical Periodontitis in Brazilians

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Abstract

Aim

To investigate if there was an association between genetic polymorphisms in TNF-⍺ and its receptors TNFRSF1A and TNFRSF1B with persistent apical periodontitis (PAP) in Brazilian subjects.

Methodology

Patients who had pulpal necrosis and apical periodontitis installed at the time of treatment, with at least one-year of follow-up after non-surgical root canal treatment were recalled. 378 subjects were included, 150 subjects with signs/symptoms of PAP and 228 subjects with root canal–treated teeth exhibiting healthy perirradicular tissues (healed). Genomic DNA was extracted from saliva and used for TNF-⍺ (rs1800629), TNFRSF1A (rs1800693) and TNFRSF1B (rs1061622) genotyping by real-time PCR. Genotypes and alleles frequencies were evaluated by c2 or Fisher's exact tests and odds ratio were implemented (𝛂= 5%).

Results

The genetic polymorphism in TNF-α (rs1800629) was associated as a protective factor for the development of PAP (p<0.05), once subjects who presented at least one allele A (AA+AG X GG), had a higher chance to lesion repair (p<0.05). The polymorphisms rs1800693 and rs1061622 in TNF receptors (TNFRSF1A and TNFRSF1B respectively) were not associated with the development of PAP (p>0.05).

Conclusions

The observed results demonstrate that polymorphism in TNF-α but not in its receptors is associated with PAP.
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